Precision Oncology Approaches for Immunotherapy

Eric H. Rubin, M.D.

MSD

Disclosures

• Employee of MSD

• Will discuss indications for pembrolizumab that are approved in U.S. but not E.U.

Using Predictive Biomarkers (Companion Diagnostics) to Select Patients for Treatment

• Cancer therapeutics are increasingly being developed together with tests that enable identification of patients most likely to benefit from the treatment

• “No test is perfect, but some tests are useful”

– Histology is an imperfect biomarker that is used to select cancer patients for treatment

• Companion diagnostics increasingly used to select among treatment options

– For both “targeted” therapeutics as well as immuno-oncology agents

• Companion diagnostic development typically lags behind therapeutics, creating scientific and regulatory complexity

The PD-1 and PD-L1/L2 Pathway

• PD-1 is an immune checkpoint receptor

• Binding of PD-1 by its ligands PD-L1 or PD-L2 leads to downregulation of T-cell function

• This mechanism is usurped by many tumors

• PD-1 blockade through mAb therapy can restore and revealeffective anti-tumor immunity

Topalian et al. N Engl J Med. 2012.

Garon et al. N Engl J Med. 2015.

Robert et al. Lancet. 2014.

Goal is to identify patients most likely to benefit from

treatment

Tumor Inflammation

PD-L1 Expression

Immune-Related Gene Expression (GEP) Signature

Tumor Antigenicity

Microsatellite instability, DNA

Mismatch Repair Deficiency, Tumor Mutation Burden

(TMB)

Potential Mechanism-based Predictive Biomarkers for Checkpoint Inhibitors

Predictive Biomarkers Important for Several Pembrolizumab Approvals

Melanoma

✓ 1st approval of a PD-1 inhibitor (US)

✓ 1L and 2L – full approval

Lung

✓ Approved for 2L TPS > 1% (US/EU/JPN)

✓ Approved for 1L TPS > 50% (US/JPN/EU)

✓ Approved 1L non-squamous NSCLC, combination with pemetrexed and carboplatin (US)

Other Tumors

✓ Approved for Head & Neck 2L (US)

✓ Approved for Relapsed or Refractory Hodgkin Lymphoma (US/EU)

✓ Approved for 1L Cis-ineligible Bladder Cancer and 2L Metastatic Bladder Cancer (US/EU)

✓ Approved for Microsatellite Instability High/Deficient in Mismatch Repair Cancer (US)

✓ Approved for Recurrent or Advanced Gastric or GE Junction Adenocarcinoma CPS > 1 (US)

✓ Approved for Previously Treated Patients with Recurrent or Metastatic Cervical CPS > 1 (US)

Blue text indicates predictive biomarker required for approval

First PD-1/L1 Companion Diagnostic Approved -22C3 pharmDx IHC Assay for Use in NSCLC

No PD-L1

Expression

Low PD-L1

Expression

High PD-L1

Expression

Correlation with Improved Outcomes to Pembrolizumab

Adapted from presentation by Garon EB AACR 2015

10x

magnification

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magnification

Utility of 22C3 pharmDx IHC Assay for Monotherapy Pembrolizumab in 1L NSCLC

Updated data show median OS of 30 months for pembrolizumab versus 14.2 months for chemotherapy

October 2016

US FDA approves pembrolizumab in the first-line treatment of patients with NSCLC(PD-L1 TPS≥50% tumor proportion score)

Presented by Brahmer J, et al at WCLC 2017

Use of Combinations to Expand the Population that BenefitsRisk of death for chemotherapy halved by combining pembrolizumab with chemotherapy in 1L metastatic NSCLC (KEYNOTE-189)

Ghandi L, et al. 2018 AACR Annual Meeting

Overall Survival Benefit Observed Irrespective of PD-L1 TPS (Keynote 189)

Ghandi L, et al. 2018 AACR Annual Meeting

On May 23, 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, regardless of tumor site or histology

What about Biomarkers Related to Tumor Antigenicity?

DNA Microsatellites

• Small, repetitive sequences, principally of polyadenine tracts1

• Abundant throughout the genome; polymorphic between individuals, but unique and uniform in length in each person1

1.Boland CR, Goel A. Gastroenterology. 2010;138(6):2073–2087.

2.Gelsomino F, et al. Cancer Treat Rev. 2016;51:19-26.

3.Dudley JC, et al. Clin Cancer Res. 2016;22(4):813-820.

Mismatchrepair

deficiency

Frameshiftmutations

Reprinted with permission from Dudley JC, et al. Clin Cancer Res

2016;22(4): 813-820.

• Microsatellites are prone to

mutations when there are deficiencies in

DNA mismatch repair (dMMR)2

MMRProteins

MMRDeficiency

DNA polymerase

errors

Microsatellite Mutations are Usually Corrected by MMR Machinery

• During replication, incorrect DNA alignment and polymerase errors can lead to insertions/deletions1

• Mismatch repair proteins MLH1, MSH2, MSH6, PMS2 correct these errors2

• MMR deficiency due to loss of repair protein expression or function causes MSI phenotype1

A10

T10

A9

T10

A9

T9

Wild type Heteroduplex Full mutant

DNA mutations cause

protein neo-antigens,

detected as ‘foreign’ &

destroyed by T- cells5

Microsatellite

Instability

1. Sinicrope FA, et al. Clin Cancer Res. 2012;18(6):1506-512.

2. Gelsomino F, et al. Cancer Treat Rev . 2016; 19-26.

3. Chung DC, et al. Ann Intern Med. 2003;138(7):560-570.

4. Kirkpatrick DT, et al. Nature. 1997;387(6636):929-931.

5. Yarchoan M, et al. Nature Rev Cancer. 2017;17(4):209-222.

Adapted from Chung et al. 2003; Kirkpatrick et al. 1997.3,4

MSI-H Phenotype May Confer Responsiveness to PD-1 Inhibition Independent of Histology

• Hypothesis: Since the target is immune

cells, PD-1 inhibition is effective in

treating any MSI-H cancer

– Regardless of tumor histology high

neoantigen expression leads to

autologous immune recognition of

cancer cells, and cytotoxic T-lymphocyte

rich microenvironment within the tumor

– Blocking PD-1 on tumor neoantigen-

specific T cells may activate anti-tumor

immune responses

Dudley JC et al. Clin Cancer Res 2016;22:813-820

Results from an MSD-Supported Investigator-Initiated Trial of Pembrolizumab in MSI-H Cancer

• MSD-supported, investigator-initiated trial (KN-016) at Johns Hopkins University – initial detection of consistent efficacy signal in a biomarker-defined population across tumor histologies

Colorectal Cancers

• Mismatch repair testing was performed locally using standard IHC for MMR deficiency or PCR-based test for microsatellite instability

KN-016 Study Design

Cohort ADeficient in

Mismatch Repair(n=25)

Cohort BProficient in

Mismatch Repair(n=25)

Non-Colorectal Cancers

Cohort CDeficient in

Mismatch Repair(n=21)

-1 0 0

-5 0

0

5 0

1 0 0

M M R -p ro fic ie n t C R C

M M R -d e fic ie n t C R C

% C

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SL

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KN-016 CRC: Best Radiographic Response

KN-016 MSI-H/dMMR non-CRC: Best Radiographic Response

Pembrolizumab Response by Tumor Type -FDA Filing (15 tumor types)

Objective response rate DOR range

N n (%) 95% CI (months)

CRC 90 32 (36%) (26%, 46%) (1.6+, 22.7+)

Non-CRC 59 27 (46%) (33%, 59%) (1.9+, 22.1+)

Endometrial cancer 14 5 (36%) (13%, 65%) (4.2+, 17.3+)

Biliary cancer 11 3 (27%) (6%, 61%) (11.6+, 19.6+)

Gastric or GE junction

cancer

9 5 (56%) (21%, 86%) (5.8+, 22.1+)

Pancreatic cancer 6 5 (83%) (36%, 100%) (2.6+, 9.2+)

Small intestinal cancer 8 3 (38%) (9%, 76%) (1.9+, 9.1+)

CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE

= not evaluable.

Source: USPI

Pembrolizumab Response by Tumor Type -FDA Filing (15 tumor types) - continued

Objective response rate DOR range

N n (%) 95% CI (months)

Non-CRC (continued) 59 27 (46%) (33%, 59%) (1.9+, 22.1+)

Breast cancer 2 PR, PR (7.6, 15.9)

Prostate cancer 2 PR, SD 9.8+

Bladder cancer 1 NE

Esophageal cancer 1 PR 18.2+

Sarcoma 1 PD

Thyroid cancer 1 NE

Retroperitoneal

adenocarcinoma

1 PR 7.5+

Small cell lung cancer 1 CR 8.9+

Renal cell cancer 1 PD

CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not

evaluable.

Source: USPI

Pooled DOR Results for Patients with MSI-H/dMMRCancer

Confirmed responses are durable

Median DOR (mos): Not reached (1.6+ - 22.7+)

Number (KM %) responders ≥6 mos: 46 (78%)

Pembrolizumab MSI-H/dMMR Efficacy Conclusions

• MSI-H phenotype represents a unique immunobiology that implicates the roles of high mutational load and responsiveness to immune checkpoint blockade regardless of cancer histology

• MSI-H cancer patients treated with chemotherapy in the second-line and later settings - associated with poor clinical outcomes, including low ORRs, brief DORs (< 6 m) and significant toxicity

• Durable clinical responses were demonstrated in 5 pembrolizumab studies in 149 subjects with15 different types of MSI-H cancer

• Pooled ORR across all trials: ORR 39.6% (95% CI:31.7, 47.9); 7.4% of subjects achieved a CR

• DOR range (range 1.6+ - 22.7+months)

• In second-line and later settings, pembrolizumab provides meaningful clinical benefit to patients with MSI-H cancer

Increasing Complexity of Companion/Complementary Diagnostics in Immuno-Oncology

Multiple FDA-Approved PD-L1 IHC Assays and Cutoffs: 22-C3, 28-8, SP-263,and SP-142 Assays

Agent Pembrolizumab Nivolumab Durvalumab Atezolizumab

Diagnostic

Platform

Dako Ventana

Antibody 22-C3 28-8 SP-263 SP-142

Cut-off(s)

being tested

TC1 1%, 50%

CPS3 1, 10

TC 1%, 5% or

10%

TC1 25% TC1 or IC2 1%,

5%,10%

1) TC = tumor cell staining.

2) IC = infiltrating immune cell staining

3) Combined positive score (tumor and immune cell staining)

AACR-sponsored “Blueprint” project designed to compare the 4 assays

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Multiple Assays under Development for Evaluation of Tumor Mutational Burden (TMB)

Company Panel Name Regulatory

Status

Panel Size

Foundation Medicine FoundationOne (F1) CDx IVD 324 genes

Foundation Medicine Blood TMB assay LDT 394 genes

Caris Life Sciences Molecular Intelligence Profile LDT 592 genes

NeoGenomics NeoTYPE Discovery Profile

NeoTYPE Solid Tumor

Profiles

Standalone

LDT Various,

Unspecified

Quest Diagnostics Watson Genomics LDT 50 genes

Memorial Sloan

Kettering

MSK-IMPACT 510(k) 468 genes

Illumina TruSight Tumor 170 RUO 170 genes

ThermoFisher Oncomine Tumor Mutation

Load

RUO 1.7 Mb

• Various studies evaluating TMB as a predictive marker for IO

treatments have used different scoring approaches and cutoffs, making

direct comparisons of the assays difficult

• Ongoing effort led by the Friends of Cancer Research, with inclusion of

FDA, and several Pharma and Diagnostics companies, to create a set

of standards for the calculation and reporting of TMB

The Ultimate in Precision Oncology -Personalized Cancer Vaccines?

Next Generation

Sequencing (NGS)What are the mutations?

Vaccine DesignWhich mutations are predicted to be the most immunogenic?

What is the best design for a drug to present these mutations to the immune system?

ManufacturingOne manufacturing batch

per patient rather than

one batch for many

patients

AdministrationBy health care

professionals

Tissue SamplesTumor (biopsy) and

normal (blood)

mRNA encoding 20 neoantigens

A personalized cancer vaccine

Slide courtesy of Tal Zaks

Moderna’s mRNA Vaccines Designed to Direct T Cells towards Cancer Killing

•Up to 20 different neoantigens for each patient in a single mRNA construct based on mutations identified by NGS sequencing of tumor

•Encapsulated in formulated lipid nanoparticles

•Designed to express neoantigens that will instruct the immune system to recognize cancerous tissue as foreign

What is mRNA-4157?

Moderna-Merck Phase I study ongoing – Keynote 603

Summary

• Multiple biomarkers have potential to help identify patients most likely to benefit from immuno-oncology treatments

• PD-L1 IHC is most advanced (approved as companion/ complementary diagnostics) and widely available

• MSI-H/dMMR assays provided a basis for the first tissue/site agnostic indication approved by FDA

• Multiple additional potential predictive biomarkers, including TMB, are under investigation

• Personalized cancer vaccines are under investigation and represent an exemplar of precision immuno-oncology approaches